US 8,552,032 B2 · Assignee: Janssen Pharmaceutica NV · Inventors: Lawson; Edward C. et al.
Claude can sketch it from the patent text.
The present invention is directed to novel bicyclic derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by DPP-1.
Chronic Obstructive Pulmonary Disease (COPD) is characterized by the progressive development of irreversible airflow limitation. COPD consists of chronic obstructive bronchitis, with obstruction of small airways, and emphysema, with enlargement of air spaces and destruction of lung parenchyma, loss of lung elasticity, and closure of small airways. In COPD patients, there were increased numbers of neutrophils, cytotoxic T lymphocytes and macrophages in bronchioalveolar lavage (BAL) airways and lung parenchyma. The presence of these inflammatory cells is correlated well with severity of airway obstruction and alveolar wall destruction. It has been shown that neutrophil elastase; cathepsin G and proteinase 3 can produce emphysema and mucus hypersecretion in lab animals. Granzymes A & B are the neutral serine proteases that are expressed exclusively in the granules of activated cytotoxic T l
Ask Claude for concept sketches based only on the patent's text. They are not part of the patent.
What the patent claimed, word for word. All of it is now free to use.
The present invention is directed to novel bicyclic derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by DPP-1.
Chronic Obstructive Pulmonary Disease (COPD) is characterized by the progressive development of irreversible airflow limitation. COPD consists of chronic obstructive bronchitis, with obstruction of small airways, and emphysema, with enlargement of air spaces and destruction of lung parenchyma, loss of lung elasticity, and closure of small airways. In COPD patients, there were increased numbers of neutrophils, cytotoxic T lymphocytes and macrophages in bronchioalveolar lavage (BAL) airways and lung parenchyma. The presence of these inflammatory cells is correlated well with severity of airway obstruction and alveolar wall destruction. It has been shown that neutrophil elastase; cathepsin G and proteinase 3 can produce emphysema and mucus hypersecretion in lab animals. Granzymes A & B are the neutral serine proteases that are expressed exclusively in the granules of activated cytotoxic T lymphocytes. In COPD the protease-antiprotease balance appears to be tipped in favor of increased proteolysis due to increase in polymorphonuclear neutrophil (PMN)-derived proteases, cathepsins and matrix metalloproteases (MMPs). Therefore, a drug that inhibits all or most of the relevant proteases mentioned above is expected to be effective in the treatment of COPD.
Dipeptidyl Peptidase-1 (DPP-1, cathepsin C) is a member of the lysosomal papain-type cysteine protease family that also includes cathepsin B, K, H, L, O, and S. DPP-1 (MW 200 kd) is composed of a dimer of disulfide-linked heavy and light chains, both from a single protein precursor. DPP-1 mRNA is highly expressed in tissues such as lung, spleen, kidney and liver; in inflammatory cells such as PMN, cytotoxic T lymphocytes, alveolar macrophages and mast cells. The biological function of DPP-1 is to convert inactive proenzymes into active enzyme by removing a dipeptide from N-terminal. The proenzymes that are activated by DPP-1 are PMN-derived proteases, granzymes A & B, chymase and tryptase. Since these enzymes play an important pathological role in COPD, inhibition of DDP-1 by small molecules would be a rational therapeutic intervention for COPD. Additional therapeutic indications for a DPP-1 inhibitor are asthma, rhinitis, and rheumatoid arthritis.
There remains a need for inhibitors of DPP-1 for the treatment of DPP-1 mediated disorders and conditions, including but not limited to rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, sepsis, irritable bowel disease, cystic fibrosis, and abdominal aortic aneurism.
The present invention is directed to compounds of formula (I)
wherein
R.sup.1 is selected from the group consisting of C.sub.1-4alkyl, --C(O)--NH.sub.2, C.sub.3-6cycloalkyl, phenyl and 5 to 6 membered heteroaryl; wherein the heteroaryl is optionally substituted with one or more substituents independently selected from halogen and C.sub.1-4alkyl;
n is an integer from 0 to 1;
L is selected from the group consisting of
##STR00002## --CH.sub.2CH.sub.2--NR.sup.A-- and --CH.sub.2CH.sub.2CH.sub.2--NR.sup.A--; wherein R.sup.A is selected from the group consisting of hydrogen, methyl and ethyl; (and wherein the L substituent group is incorporated into the compound of formula (I) as drawn; more particularly, the L substituent group is incorporated into the compound of formula (I) such that the N atom of the L substituent group is bound to the C(O) of the compound of formula (I))
Y is selected from the group consisting of N and CH;
X is selected from the group consisting of N(R.sup.B), O and S; wherein R.sup.B is selected from the group consisting of hydrogen and C.sub.1-4alkyl;
R.sup.2 is selected from the group consisting of hydrogen, halogen, nitro, --CO.sub.2H, --C(O)--NR.sup.CR.sup.D, -Q, --O-Q and --C(O)--NH-Q;
wherein R.sup.C and R.sup.D are each independently selected from the group consisting of hydrogen and C.sub.1-4alkyl; alternatively, R.sup.C and R.sup.D are taken together with the nitrogen atom to which they are bound to form a ring structure selected from the group consisting of piperidin-1-yl, piperazin-1-yl, pyrrolidin-1-yl, morpholin-4-yl, 1,2,3,4-tetrahydroquinolin-1-yl and 1,2,3,4-tetrahydro-isoquinolin-2-yl;
wherein Q is selected from the group consisting of aryl, aralkyl, heterocyclyl, benzo[d][1,3]dioxolyl and 2,3-dihydro-benzo[b][1,4]dioxinyl;
wherein the aryl or heterocyclyl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C.sub.1-4alkyl, halogenated C.sub.1-4alkyl, C.sub.1-4alkoxy, halogenated C.sub.1-4alkoxy, --CO.sub.2H, --C(O)--NR.sup.ER.sup.F, --SO.sub.2--NR.sup.ER.sup.F and phenyl; wherein R.sup.E and R.sup.F are each independently selected from the group consisting of hydrogen and C.sub.1-4alkyl;
and wherein the heterocyclyl contains one or more S heteroatoms, said heterocyclyl may be further optionally substituted on said one or more S heteroatoms with one to two oxo groups;
and pharmaceutically acceptable salts thereof.
The present invention is further directed to compounds of formula (II)
wherein
R.sup.1 is selected from the group consisting of C.sub.1-4alkyl, --C(O)--NH.sub.2, C.sub.3-6cycloalkyl, phenyl and 5 to 6 membered heteroaryl; wherein the heteroaryl is optionally substituted with one or more substituents independently selected from halogen and C.sub.1-4alkyl;
n is an integer from 0 to 1;
L is selected from the group consisting of --CH.sub.2CH.sub.2--NR.sup.A-- and --CH.sub.2CH.sub.2CH.sub.2--NR.sup.A--; wherein R.sup.A is selected from the group consisting of hydrogen, methyl and ethyl; (and wherein the L substituent group is incorporated into the compound of formula (I) as drawn; more particularly, the L substituent group is incorporated into the compound of formula (I) such that the N atom of the L substituent group is bound to the C(O) of the compound of formula (I))
X is selected from the group consisting of N(R.sup.B), O and S; wherein R.sup.B is selected from the group consisting of hydrogen and C.sub.1-4alkyl;
R.sup.2 is selected from the group consisting of hydrogen, halogen, nitro, --CO.sub.2H, --C(O)--NR.sup.CR.sup.D, -Q, --O-Q and --C(O)--NH-Q;
wherein R.sup.C and R.sup.D are each independently selected from the group consisting of hydrogen and C.sub.1-4alkyl; alternatively, R.sup.C and R.sup.D are taken together with the nitrogen atom to which they are bound to form a ring structure selected from the group consisting of piperidin-1-yl, piperazin-1-yl, pyrrolidin-1-yl, morpholin-4-yl, 1,2,3,4-tetrahydroquinolin-1-yl and 1,2,3,4-tetrahydro-isoquinolin-2-yl;
wherein Q is selected from the group consisting of aryl, aralkyl, heterocyclyl, benzo[d][1,3]dioxolyl and 2,3-dihydro-benzo[b][1,4]dioxinyl;
wherein the aryl or heterocyclyl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C.sub.1-4alkyl, halogenated C.sub.1-4alkyl, C.sub.1-4alkoxy, halogenated C.sub.1-4alkoxy, --CO.sub.2H, --C(O)--NR.sup.ER.sup.F, --SO.sub.2--NR.sup.ER.sup.F and phenyl; wherein R.sup.E and R.sup.F are each independently selected from the group consisting of hydrogen and C.sub.1-4alkyl;
and wherein the heterocyclyl contains one or more S heteroatoms, said heterocyclyl may be further optionally substituted on said one or more S heteroatoms with one to two oxo groups;
and pharmaceutically acceptable salts thereof.
The present invention is further directed to processes for the preparation of the compounds of formula (I) and/or the compounds of formula (II). The present invention is further directed to a product prepared according to the process described herein.
Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product prepared according to the process described herein. An illustration of the invention is a pharmaceutical composition made by mixing the product prepared according to the process described herein and a pharmaceutically acceptable carrier. Illustrating the invention is a process for making a pharmaceutical composition comprising mixing the product prepared according to the process described herein and a pharmaceutically acceptable carrier.
Exemplifying the invention are methods of treating a disorder mediated by DPP-1 (cathepsin C) (e.g., a disorder selected from the group consisting of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, sepsis, irritable bowel disease, cystic fibrosis, and abdominal aortic aneurism) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.
Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: (a) rheumatoid arthritis, (b) asthma, (c) chronic obstructive pulmonary disease, (d) sepsis, (e) irritable bowel disease, (f) cystic fibrosis, or (g) abdominal aortic aneurism, in a subject in need thereof.
In another example, the present invention is directed to a compound as described herein for use in a methods for treating a disorder selected from the group consisting of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, sepsis, irritable bowel disease, cystic fibrosis, and abdominal aortic aneurism, in a subject in need thereof.
The present invention is directed to compounds of formula (I)
wherein R.sup.1, R.sup.2, X, Y, L and n are as herein defined, and pharmaceutically acceptable salts thereof. The present invention is further directed to compounds of formula (II)
wherein R.sup.1, R.sup.2, X, Y, L and n are as herein defined, and pharmaceutically acceptable salts thereof. The compounds of formula (I) and formula (II) of the present invention are inhibitors of DPP-1, useful in the treatment of disorders, diseases and conditions mediated by DPP-1 (cathepsin C), including, but not limited to, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, sepsis, irritable bowel disease, cystic fibrosis, and abdominal aortic aneurism.
One skilled in the art will recognize that some of the variables (e.g. R.sup.1, R.sup.2, X, L and n, etc.) appear in compounds of formula (I) and compounds of formula (II). One skilled in the art will further recognize that wherein a particular substituent is selected for a given variable for a compound of formula (I), said selection is not intended to limit the scope of said variable for compounds of formula (II). Similarly, the selection of a particular substituent for a given variable for a compound of formula (II), is not intended to limit the scope of said variable for compounds of formula (I).
In an embodiment of the present invention, R.sup.1 is selected from the group consisting of C.sub.1-4alkyl, --C(O)--NH.sub.2, C.sub.3-6cycloalkyl and 5 to 6 membered heteroaryl; wherein the 5 to 6 membered heteroaryl is optionally substituted with one to two substituent selected from the group consisting of halogen and C.sub.1-4alkyl. In another embodiment of the present invention, R.sup.1 is selected from the group consisting of C.sub.1-4alkyl, --C(O)--NH.sub.2, C.sub.4-6cycloalkyl and 5 to 6 membered heteroaryl; wherein the 5 to 6 membered heteroaryl is optionally substituted with a substituent selected from the group consisting of halogen and C.sub.1-4alkyl.
In another embodiment of the present invention, R.sup.1 is selected from the group consisting of ethyl, cyclobutyl, thien-2-yl, thien-3-yl, 2-bromo-thien-2-yl, 5-chloro-thien-2-yl, thiazol-2-yl, 4-methyl-thiazol-2-yl, pyrazol-1-yl, fur-2-yl, 1-methyl-imidazol-4-yl and amino-carbonyl. In another embodiment of the present invention, R.sup.1 is selected from the group consisting of ethyl, thien-2-yl, thiazol-2-yl, fur-2-yl and 1-methyl-imidazol-4-yl. In another embodiment of the present invention, R.sup.1 is selected from the group consisting of ethyl, thien-2-yl, thiazol-2-yl and fur-2-yl. In another embodiment of the present invention, R.sup.1 is selected from the group consisting of ethyl, thien-2-yl and thiazol-2-yl. In another embodiment of the present invention, R.sup.1 is thien-2-yl.
In another embodiment of the present invention, R.sup.1 is C.sub.1-4alkyl. In another embodiment of the present invention, R.sup.1 is C.sub.1-2alkyl. In another embodiment of the present invention, R.sup.1 is ethyl.
In an embodiment of the present invention n is 0. In another embodiment of the present invention, n is 1.
In an embodiment of the present invention, L is
##STR00006## In another embodiment of the present invention, L is selected from the group consisting of --CH.sub.2CH.sub.2--N(R.sup.A)-- and --CH.sub.2CH.sub.2CH.sub.2--N(R.sup.A)--; wherein R.sup.A is selected from the group consisting of hydrogen, methyl and ethyl. In another embodiment of the present invention, L is --CH.sub.2CH.sub.2CH.sub.2--N(R.sup.A)--; wherein R.sup.A is selected from the group consisting of hydrogen, methyl and ethyl. In another embodiment of the present invention, L is --CH.sub.2CH.sub.2--NR.sup.A--. In another embodiment of the present invention, L is --CH.sub.2CH.sub.2CH.sub.2--NR.sup.A--. In another embodiment of the present invention, L is --CH.sub.2CH.sub.2CH.sub.2--NH--.
In an embodiment of the present invention, L is selected from the group consisting of
##STR00007## --CH.sub.2CH.sub.2--N(R.sup.A)-- and --CH.sub.2CH.sub.2CH.sub.2--N(R.sup.A)--; wherein R.sup.A is selected from the group consisting of hydrogen, methyl and ethyl. In another embodiment of the present invention, L is selected from the group consisting of
##STR00008## --CH.sub.2CH.sub.2--NH--, --CH.sub.2CH.sub.2CH.sub.2--NH--, --CH.sub.2CH.sub.2CH.sub.2--N(CH.sub.3)-- and --CH.sub.2CH.sub.2CH.sub.2--N(CH.sub.2CH.sub.3)--. In another embodiment of the present invention, L is selected from the group consisting of
##STR00009## --CH.sub.2CH.sub.2--NH--, --CH.sub.2CH.sub.2CH.sub.2--NH-- and --CH.sub.2CH.sub.2CH.sub.2--N(CH.sub.2CH.sub.3)--. In another embodiment of the present invention, L is selected from the group consisting of
##STR00010## --CH.sub.2CH.sub.2CH.sub.2--NH-- and --CH.sub.2CH.sub.2CH.sub.2--N(CH.sub.2CH.sub.3)--. In another embodiment of the present invention, L is selected from the group consisting of
##STR00011## and --CH.sub.2CH.sub.2CH.sub.2--NH--.
In an embodiment of the present invention, R.sup.A is selected from the group consisting of hydrogen, methyl and ethyl. In another embodiment of the present invention, R.sup.A is hydrogen.
In an embodiment of the present invention
##STR00012## is selected from the group consisting of indolyl, 1-methyl-indolyl, benzofuryl, benzothienyl and benzimidazolyl.
In an embodiment of the present invention, Y is selected from the group consisting of N and CH; and X is selected from the group consisting of N(R.sup.B), O and S; provided that when X is O or S, then Y is CH.
In an embodiment of the present invention Y is N. In another embodiment of the present invention, Y is CH. In an embodiment of the present invention X is O. In another embodiment of the present invention, X is S. In another embodiment of the present invention, X is NR.sup.B. In another embodiment of the present invention, R.sup.B is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl and t-butyl. In another embodiment of the present invention, R.sup.B is selected from the group consisting of hydrogen, methyl and ethyl. In another embodiment of the present invention, R.sup.B is selected from the group consisting of hydrogen and methyl. In another embodiment of the present invention, R.sup.B is hydrogen.
In an embodiment of the present invention, Y is selected from the group consisting of N and CH; and X is selected from the group consisting of N(R.sup.B), O and S; wherein R.sup.B is selected from the group consisting of hydrogen and C.sub.1-2alkyl. In another embodiment of the present invention, Y is selected from the group consisting of CH and N; and X is selected from the group consisting of NH, N(CH.sub.3) and O; provided that when X is O, then Y is CH. In another embodiment of the present invention, Y is selected from the group consisting of CH and N; and X is selected from the group consisting of NH and O; provided that when X is O, then Y is CH. In another embodiment of the present invention, Y is CH; and X is NH.
In an embodiment of the present invention
##STR00013## is selected from the group consisting of indolyl and benzothienyl. In another embodiment of the present invention, X is selected from the group consisting of N(R.sup.B) and S; wherein R.sup.B is selected from the group consisting of hydrogen and C.sub.1-2alkyl. In another embodiment of the present invention, X is selected from the group consisting of S and NH.
In an embodiment of the present invention, R.sup.2 is selected from the group consisting of hydrogen, halogen, nitro, --CO.sub.2H, --C(O)--NR.sup.CR.sup.D, phenyl, --O-phenyl, heterocyclyl, and --C(O)--NH-Q; wherein R.sup.C and R.sup.D are each independently selected from the group consisting of hydrogen and C.sub.1-4alkyl; alternatively, R.sup.C and R.sup.D are taken together with the nitrogen atom to which they are bound to form a ring structure selected from the group consisting of piperidin-1-yl, pyrrolidin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl and 1,2,3,4-tetrahydro-isoquinolin-2-yl;
wherein Q is selected from the group consisting of aryl, aralkyl, heterocyclyl, benzo[d][1,3]dioxolyl and 2,3-dihydro-benzo[b][1,4]dioxinyl; wherein the aryl or heterocyclyl, whether alone or as part of a substituent group, is optionally substituted with one to two substituents independently selected from the group consisting of halogen, cyano, C.sub.1-4alkyl, fluorinated C.sub.1-4alkyl, C.sub.1-4alkoxy, fluorinated C.sub.1-4alkoxy, --CO.sub.2H, --C(O)NR.sup.ER.sup.F, --SO.sub.2--NR.sup.ER.sup.F and phenyl; wherein R.sup.E and R.sup.F are each independently selected from the group consisting of hydrogen and C.sub.1-2alkyl; and wherein the heterocyclyl contains one or more S heteroatoms, said heterocyclyl may be further optionally substituted on said one or more S heteroatoms with one to two oxo groups.
In another embodiment of the present invention, R.sup.2 is selected from the group consisting of hydrogen, halogen, nitro, carboxy, phenyl, --O-phenyl, --C(O)--NR.sup.CR.sup.D and --C(O)--NH-Q; wherein R.sup.C and R.sup.D are each independently selected from the group consisting of hydrogen and C.sub.1-2alkyl; alternatively, R.sup.C and R.sup.D are taken together with the nitrogen atom to which they are bound to form a ring structure selected from the group consisting of 1,2,3,4-tetrahydroquinolin-1-yl and 1,2,3,4-tetrahydro-isoquinolin-2-yl;
wherein Q is selected from the group consisting of phenyl, naphthyl, --C.sub.1-2alkyl-phenyl, heterocyclyl, benzo[d][1,3]dioxolyl and 2,3-dihydro-benzo[b][1,4]dioxinyl; wherein the phenyl or heterocyclyl, whether alone or as part of a substituent group, is optionally substituted with one to two substituents independently selected from the group consisting of halogen, cyano, C.sub.1-4alkyl, fluorinated C.sub.1-2alkyl, C.sub.1-4alkoxy, fluorinated C.sub.1-2alkoxy, --CO.sub.2H, --C(O)NH.sub.2, --SO.sub.2--NH.sub.2 and phenyl; and wherein the heterocyclyl contains one or more S heteroatoms, said heterocyclyl may be further optionally substituted on said one or more S heteroatoms with one to two oxo groups.
In another embodiment of the present invention, R.sup.2 is selected from the group consisting of hydrogen, 5-bromo, 5-(carboxy), 5-(nitro), 5-(phenyl), 5-(4-fluorophenyl), 5-(4-methoxy-phenyl), 5-(3,4-dimethoxy-phenyl), 5-(3,5-dimethoxy-phenyl), 5-(3-cyano-phenyl), 5-(3-carboxy-phenyl), 5-(4-carboxy-phenyl), 5-(4-trifluoromethyl-phenyl), 5-(4-trifluoromethoxy-phenyl), 5-(3,5-di(trifluoromethyl)-phenyl), 5-(2-(aminocarbonyl)-phenyl), 5-(3-(aminocarbonyl)-phenyl), 5-(4-(aminocarbonyl)-phenyl), 5-(3-(aminosulfonyl)-phenyl), 5-(phenoxy), 5-(3,4-dimethoxy-phenoxy), 6-(diethylamino-carbonyl), 5-(phenyl-amino-carbonyl), 5-(3-chlorophenyl-amino-carbonyl), 5-(4-chlorophenyl-amino-carbonyl), 5-(2-fluorophenyl-amino-carbonyl), 5-(3-fluorophenyl-amino-carbonyl), 5-(4-fluorophenyl-amino-carbonyl), 5-(3-methylphenyl-amino-carbonyl), 5-(4-methylphenyl-amino-carbonyl), 5-(2-isopropylphenyl-amino-carbonyl), 5-(4-isopropylphenyl-amino-carbonyl), 5-(4-t-butylphenyl-amino-carbonyl), 5-(2-methoxyphenyl-amino-carbonyl), 5-(3-methoxyphenyl-amino-carbonyl), 5-(4-methoxyphenyl-amino-carbonyl), 5-(3,4-difluorophenyl-amino-carbonyl), 5-(3,4-dichlorophenyl-amino-carbonyl), 5-(3,4-dimethylphenyl-amino-carbonyl), 5-(2,6-dimethylphenyl-amino-carbonyl), 5-(3,4-dimethoxyphenyl-amino-carbonyl), 5-(3,5-dimethoxyphenyl-amino-carbonyl), 5-(naphth-1-yl-amino-carbonyl), 5-(benzyl-amino-carbonyl), 5-([1,2,4]triazol-3-yl-amino-carbonyl), 5-(pyrid-3-yl-amino-carbonyl), 5-(quinolin-3-yl-amino-carbonyl), 5-(quinolin-5-yl-amino-carbonyl), 5-(quinolin-6-yl-amino-carbonyl), 5-(quinolin-8-yl-amino-carbonyl), 5-(isoquinolin-5-yl-amino-carbonyl), 5-(isoquinolin-8-yl-amino-carbonyl), 5-(benzothiazol-6-yl-amino-carbonyl), 5-(benzimidazol-4-yl-amino-carbonyl), 5-(benzimidazol-5-yl-amino-carbonyl), 5-(1-methyl-benzimidazol-4-yl-amino-carbonyl), 5-(pyrazol-3-yl-amino-carbonyl), 5-(5-phenyl-pyrazol-3-yl-amino-carbonyl), 5-(1H-pyrazolo[3,4-d]pyrimidin-4-yl-amino-carbonyl), 5-(1,1-dioxo-benzothiophen-6-yl-amino-carbonyl), 5-(1,2,3,4-tetrahydro-quinolin-1-yl-amino-carbonyl), 5-(1,2,3,4-tetrahydro-quinolin-1-yl-carbonyl), 5-(1,2,3,4-tetrahydro-isoquinolin-2-yl-carbonyl), 5-(pyrid-3-yl), 5-(pyrid-4-yl), 5-(6-methoxy-pyrid-3-yl), 5-(2,3-dihydro-benzo[b][1,4]dioxin-6-yl) and 5-(benzo[d][1,3]dioxol-5-yl).
In another embodiment of the present invention, R.sup.2 is selected from the group consisting of hydrogen, 5-bromo, 5-(phenyl), 5-(4-fluorophenyl), 5-(4-methoxy-phenyl), 5-(3,4-dimethoxy-phenyl), 5-(3,5-dimethoxy-phenyl), 5-(3-cyano-phenyl), 5-(3-carboxy-phenyl), 5-(4-carboxy-phenyl), 5-(4-trifluoromethyl-phenyl), 5-(4-trifluoromethoxy-phenyl), 5-(3,5-di(trifluoromethyl)-phenyl), 5-(2-(aminocarbonyl)-phenyl), 5-(3-(aminocarbonyl)-phenyl), 5-(4-(aminocarbonyl)-phenyl), 5-(3-(aminosulfonyl)-phenyl), 5-(phenoxy), 5-(3,4-dimethoxy-phenoxy), 5-(phenyl-amino-carbonyl), 5-(3-chlorophenyl-amino-carbonyl), 5-(4-chlorophenyl-amino-carbonyl), 5-(2-fluorophenyl-amino-carbonyl), 5-(3-fluorophenyl-amino-carbonyl), 5-(4-fluorophenyl-amino-carbonyl), 5-(3-methylphenyl-amino-carbonyl), 5-(4-methylphenyl-amino-carbonyl), 5-(2-isopropylphenyl-amino-carbonyl), 5-(4-isopropylphenyl-amino-carbonyl), 5-(4-t-butylphenyl-amino-carbonyl), 5-(2-methoxyphenyl-amino-carbonyl), 5-(3-methoxyphenyl-amino-carbonyl), 5-(4-methoxyphenyl-amino-carbonyl), 5-(3,4-difluorophenyl-amino-carbonyl), 5-(3,4-dichlorophenyl-amino-carbonyl), 5-(3,4-dimethylphenyl-amino-carbonyl), 5-(2,6-dimethylphenyl-amino-carbonyl), 5-(3,4-dimethoxyphenyl-amino-carbonyl), 5-(3,5-dimethoxyphenyl-amino-carbonyl), 5-(naphth-1-yl-amino-carbonyl), 5-(pyrid-3-yl-amino-carbonyl), 5-(quinolin-3-yl-amino-carbonyl), 5-(quinolin-5-yl-amino-carbonyl), 5-(quinolin-6-yl-amino-carbonyl), 5-(quinolin-8-yl-amino-carbonyl), 5-(isoquinolin-5-yl-amino-carbonyl), 5-(isoquinolin-8-yl-amino-carbonyl), 5-(benzothiazol-6-yl-amino-carbonyl), 5-(benzimidazol-4-yl-amino-carbonyl), 5-(benzimidazol-5-yl-amino-carbonyl), 5-(1-methyl-benzimidazol-4-yl-amino-carbonyl), 5-(pyrazol-3-yl-amino-carbonyl), 5-(5-phenyl-pyrazol-3-yl-amino-carbonyl), 5-(1H-pyrazolo[3,4-d]pyrimidin-4-yl-amino-carbonyl), 5-(1,1-dioxo-benzothiophen-6-yl-amino-carbonyl), 5-(1,2,3,4-tetrahydro-quinolin-1-yl-amino-carbonyl), 5-(1,2,3,4-tetrahydro-quinolin-1-yl-carbonyl), 5-(1,2,3,4-tetrahydro-isoquinolin-2-yl-carbonyl), 5-(pyrid-3-yl), 5-(pyrid-4-yl), 5-(6-methoxy-pyrid-3-yl), 5-(2,3-dihydro-benzo[b][1,4]dioxin-6-yl) and 5-(benzo[d][1,3]dioxol-5-yl).
In another embodiment of the present invention, R.sup.2 is selected from the group consisting of 5-bromo, 5-(phenyl), 5-(4-fluorophenyl), 5-(4-methoxy-phenyl), 5-(3,4-dimethoxy-phenyl), 5-(3,5-dimethoxy-phenyl), 5-(3-cyano-phenyl), 5-(3-carboxy-phenyl), 5-(4-carboxy-phenyl), 5-(4-trifluoromethyl-phenyl), 5-(4-trifluoromethoxy-phenyl), 5-(3,5-di(trifluoromethyl)-phenyl), 5-(3-(aminocarbonyl)-phenyl), 5-(4-(aminocarbonyl)-phenyl), 5-(3-(aminosulfonyl)-phenyl), 5-(phenoxy), 5-(3,4-dimethoxy-phenoxy), 5-(3-chlorophenyl-amino-carbonyl), 5-(4-chlorophenyl-amino-carbonyl), 5-(3-fluorophenyl-amino-carbonyl), 5-(3-methylphenyl-amino-carbonyl), 5-(4-isopropylphenyl-amino-carbonyl), 5-(4-t-butylphenyl-amino-carbonyl), 5-(3-methoxyphenyl-amino-carbonyl), 5-(4-methoxyphenyl-amino-carbonyl), 5-(3,4-difluorophenyl-amino-carbonyl), 5-(3,4-dichlorophenyl-amino-carbonyl), 5-(3,4-dimethylphenyl-amino-carbonyl), 5-(2,6-dimethylphenyl-amino-carbonyl), 5-(3,4-dimethoxyphenyl-amino-carbonyl), 5-(naphth-1-yl-amino-carbonyl), 5-(quinolin-3-yl-amino-carbonyl), 5-(quinolin-5-yl-amino-carbonyl), 5-(quinolin-6-yl-amino-carbonyl), 5-(quinolin-8-yl-amino-carbonyl), 5-(isoquinolin-5-yl-amino-carbonyl), 5-(isoquinolin-8-yl-amino-carbonyl), 5-(benzothiazol-6-yl-amino-carbonyl), 5-(pyrid-3-yl), 5-(pyrid-4-yl), 5-(6-methoxy-pyrid-3-yl), 5-(2,3-dihydro-benzo[b][1,4]dioxin-6-yl) and 5-(benzo[d][1,3]dioxol-5-yl).
In another embodiment of the present invention, R.sup.2 is selected from the group consisting of 5-(4-methoxy-phenyl), 5-(3,4-dimethoxy-phenyl), 5-(3,5-dimethoxy-phenyl), 5-(3-cyano-phenyl), 5-(4-carboxy-phenyl), 5-(3-(aminocarbonyl)-phenyl), 5-(phenoxy), 5-(3,4-dimethoxy-phenoxy), 5-(3-methoxyphenyl-amino-carbonyl), 5-(4-methoxyphenyl-amino-carbonyl), 5-(2,6-dimethylphenyl-amino-carbonyl), 5-(3,4-dimethoxyphenyl-amino-carbonyl), 5-(quinolin-3-yl-amino-carbonyl), 5-(quinolin-5-yl-amino-carbonyl), 5-(quinolin-6-yl-amino-carbonyl), 5-(isoquinolin-5-yl-amino-carbonyl), 5-(isoquinolin-8-yl-amino-carbonyl), 5-(pyrid-3-yl), 5-(pyrid-4-yl), 5-(6-methoxy-pyrid-3-yl), 5-(2,3-dihydro-benzo[b][1,4]dioxin-6-yl) and 5-(benzo[d][1,3]dioxol-5-yl).
In another embodiment of the present invention, R.sup.2 is selected from the group consisting of 5-(3,4-dimethoxyphenyl) and 5-(3,4-dimethoxyphenyl-amino-carbonyl). In another embodiment of the present invention, R.sup.2 is hydrogen.
In an embodiment of the present invention, the R.sup.2 group is bound at the 5- or 6-position of the
##STR00014## core. In another embodiment, the R.sup.2 group is bound at the 5-position of the
##STR00015## core. In an embodiment of the present invention, the R.sup.2 group is bound at the 5- or 6-position of the
##STR00016## core. In another embodiment, the R.sup.2 group is bound at the 5-position of the
##STR00017## core.
In an embodiment, the present invention is directed to compounds of formula (I) wherein the stereo-center denoted with the "*" symbol is present in (R) configuration. Preferably, the compound of formula (I) is present in the (R) configurations in an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%.
In an embodiment, the present invention is directed to compounds of formula (I) wherein the stereo-center denoted with the "*" symbol is present in (S) configuration. Preferably, the compound of formula (I) is present in the (S) configurations in an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%.
In an embodiment, the present invention is directed to compounds of formula (II) wherein the stereo-center denoted with the "*" symbol is present in (R) configuration. Preferably, the compound of formula (II) is present in the (R) configurations in an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%.
In an embodiment, the present invention is directed to compounds of formula (II) wherein the stereo-center denoted with the "*" symbol is present in (S) configuration. Preferably, the compound of formula (II) is present in the (S) configurations in an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%.
Additional embodiments of the present invention, include those wherein the substituents selected for one or more of the variables defined herein (i.e.
##STR00018## R.sup.1, R.sup.2, L, X, Y and n) are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein. In another embodiment of the present invention is any single compound or subset of compounds selected from the representative compounds listed in Tables 1 to 4 below.
Representative compounds of formula (I) of the present invention are as listed in Tables 1 to 3 below. One skilled in the art will recognize that in the recitation of the bonding position of the R.sup.2 substituent group to the
##STR00019## core of the compounds of formula (I) (including in Tables 1 to 3 below), the position of the R.sup.2 substituent group shall be denoted according to the following numbering scheme:
One skilled in the art will further recognize that in Tables 1 to 3 which follow herein, in the column headed "R.sup.2", the recitation of #-(substituted group) shall denote the position at which the R.sup.2 group is bound to the
##STR00021## followed by the identification of the substituent group within the parentheses. For example, the notation 5-(3,4-dimethoxy-phenyl) shall denoted a 3,4-dimethoxy-phenyl group bound at the 5-position of the
##STR00022## core.
TABLE-US-00001 TABLE 1 Representative Compounds of Formula (I) ##STR00023## ID No. R.sup.2 ##STR00024## * n R.sup.1 1 hydrogen ##STR00025## S 1 thien-2-yl 2 5-(3,4-dimethoxy- phenyl) ##STR00026## S 1 thien-2-yl 3 5-(2,3-dihydro- benzo[b][1,4] dioxin-6-yl) ##STR00027## S 1 thien-2-yl 4 5-(4-methoxy- phenyl) ##STR00028## S 1 thien-2-yl 5 5-(3-(amino- carbonyl)-phenyl) ##STR00029## S 1 thien-2-yl 6 5-(benzo [d][1,3]dioxol- 5-yl) ##STR00030## S 1 thien-2-yl 7 5-((3,4-dimethoxy- phenyl)-amino- carbonyl) ##STR00031## S 1 thien-2-yl 8 5-(3-(amino- carbonyl)-phenyl) ##STR00032## S 1 thiazol-2-yl 9 5-(3,4-dimethoxy- phenyl) ##STR00033## S 0 ethyl 10 5-(3,4-dimethoxy- phenyl) ##STR00034## S 1 5-bromo- thien-2-yl 11 5-(3,4-dimethoxy- phenyl) ##STR00035## S 1 pyrazol-1-yl 12 5-(3,4-dimethoxy- phenyl) ##STR00036## S 1 cyclobutyl 13 5-(3,4-dimethoxy- phenyl) ##STR00037## S 1 fur-2-yl 14 5-(3,4-dimethoxy- phenyl) ##STR00038## S 1 1-methyl- imidazol-4- yl 15 5-(3,4-dimethoxy- phenyl) ##STR00039## S 1 thien-3-yl 16 5-bromo ##STR00040## S 1 thien-2-yl 17 5-((3,4-dimethoxy- phenyl)-amino- carbonyl) ##STR00041## S 1 thien-2-yl 18 5-(3,4-dimethoxy- phenyl) ##STR00042## S 1 thien-2-yl 19 5-(3-(amino- carbonyl)-phenyl) ##STR00043## S 1 thien-2-yl 20 5-(3-cyano-phenyl) ##STR00044## S 1 thien-2-yl 21 5-(3-carboxyl- phenyl) ##STR00045## S 1 thien-2-yl 22 5-(3,4-dimethoxy- phenyl) ##STR00046## S 1 4-methyl- thiazol-2-yl 23 5-(pyrid-3-yl) ##STR00047## S 1 thien-2-yl 24 5-(3,4-dimethoxy- phenyl) ##STR00048## S 1 5-chloro- thien-2-yl 25 5-(6-methoxy- pyrid-3-yl) ##STR00049## S 1 thien-2-yl 26 5-(pyrid-4-yl) ##STR00050## S 1 thien-2-yl 27 5-(4-carboxy- phenyl) ##STR00051## S 1 thien-2-yl 28 5-(3,4-dimethoxy- phenyl) ##STR00052## R/S 0 thien-2-yl 29 5-(3,4-dimethoxy- phenyl) ##STR00053## R/S 0 fur-2-yl 30 5-(3,4-dimethoxy- phenyl) ##STR00054## R/S 0 thien-3-yl
TABLE-US-00002 TABLE 2 Representative Compounds of Formula (I) ID No. R.sup.2 ##STR00055## * n R.sup.1 ##STR00056## 35 hydrogen ##STR00057## S 1 thien-2-yl 36 5-(3,4-dimethoxy- phenyl-amino- carbonyl) ##STR00058## S 0 ethyl 37 hydrogen ##STR00059## S 1 thien-2-yl 38 hydrogen ##STR00060## S 0 ethyl 39 hydrogen ##STR00061## S 0 ethyl ##STR00062## 40 hydrogen ##STR00063## S 0 ethyl 41 hydrogen ##STR00064## S 0 ethyl 42 hydrogen ##STR00065## S 0 ethyl 45 5-(phenyl) ##STR00066## S 0 ethyl 46 6-(diethylamino- carbonyl) ##STR00067## S 0 ethyl 47 5-(carboxy) ##STR00068## S 0 ethyl 48 5-([1,2,4]triazol-3-yl- amino-carbonyl) ##STR00069## S 0 ethyl 49 5-(nitro) ##STR00070## S 0 ethyl 50 5-(3,4-dimethoxy- phenyl-amino- carbonyl) ##STR00071## S 0 ethyl 51 5-(phenyl-amino- carbonyl) ##STR00072## S 0 ethyl 52 5-(pyrid-3-yl-amino- carbonyl) ##STR00073## S 0 ethyl 53 5-(benzyl-amino- carbonyl) ##STR00074## S 0 ethyl 54 5-(naphth-1-yl- amino-carbonyl) ##STR00075## S 0 ethyl 55 5-(quinolin-5-yl- amino-carbonyl) ##STR00076## S 0 ethyl 56 hydrogen ##STR00077## S 1 thien-2-yl 57 5-(benzothiazol-6-yl- amino-carbonyl) ##STR00078## S 0 ethyl 58 5-(3,4-dimethoxy- phenyl-amino- carbonyl) ##STR00079## S 0 ethyl 59 5-(1-methyl- benzimidazol-4-yl- amino-carbonyl) ##STR00080## S 0 ethyl 61 5-(pyrazol-3-yl- amino-carbonyl) ##STR00081## S 0 ethyl 62 5-(5-phenyl-pyrazol- 3-yl-amino-carbonyl) ##STR00082## S 0 ethyl 63 5-(1H-pyrazolo[3,4- d]pyrimidin-4-yl- amino-carbonyl) ##STR00083## S 0 ethyl 64 5-(quinolin-3-yl- amino-carbonyl) ##STR00084## S 0 ethyl 65 5-(isoquinolin-5-yl- amino-carbonyl) ##STR00085## S 0 ethyl 66 5-(quinolin-8-yl- amino-carbonyl ##STR00086## S 0 ethyl 67 5-(quinolin-6-yl- amino-carbonyl) ##STR00087## S 0 ethyl 68 5-(isoquinolin-8-yl- amino-carbonyl) ##STR00088## S 0 ethyl 69 5-(2,3-dihydro- benzo[b][1,4]dioxin- 6-yl) ##STR00089## S 0 ethyl 70 5-(benzo[d][1,3] dioxol-5-yl) ##STR00090## S 0 ethyl 71 5-(1,2,3,4-tetrahydro- quinolin-1-yl- carbonyl) ##STR00091## S 0 ethyl 72 5-(benzimidazol-5-yl- amino-carbonyl) ##STR00092## S 0 ethyl 73 5-(1,2,3,4-tetrahydro- quinolin-4-yl-amino- carbonyl) ##STR00093## S 0 ethyl 74 5-(carboxy) ##STR00094## S 0 ethyl 75 5-(4-methyl-phenyl- amino-carbonyl) ##STR00095## S 0 ethyl 76 5-(4-chloro-phenyl- amino-carbonyl) ##STR00096## S 0 ethyl 77 5-(4-methoxy-phenyl- amino-carbonyl) ##STR00097## S 0 ethyl 78 5-(4-t-butyl-phenyl- amino-carbonyl) ##STR00098## S 0 ethyl 79 5-(4-fluoro-phenyl- amino-carbonyl) ##STR00099## S 0 ethyl 80 5-(4-isopropyl- phenyl-amino- carbonyl) ##STR00100## S 0 ethyl 81 5-(3,4-difluoro- phenyl-amino- carbonyl) ##STR00101## S 0 ethyl 82 5-(3,4-dichloro- phenyl-amino- carbonyl) ##STR00102## S 0 ethyl 83 5-(3,4-dimethyl- phenyl-amino- carbonyl) ##STR00103## S 0 ethyl 84 5-(1,2,3,4-tetrahydro- isoquinolin-2-yl- carbonyl) ##STR00104## S 0 ethyl 85 5-(benzimidazol-4-yl- amino-carbonyl) ##STR00105## S 0 ethyl 86 5-(1,1-dioxo- benzothiophen-6-yl- amino-carbonyl) ##STR00106## S 0 ethyl 87 5-(2-fluorophenyl- amino-carbonyl) ##STR00107## S 0 ethyl 88 5-(2-methoxy-phenyl- amino-carbonyl) ##STR00108## S 0 ethyl 89 5-(2-isopropyl- phenyl-amino- carbonyl) ##STR00109## S 0 ethyl 90 5-(3-fluorophenyl- amino-carbonyl) ##STR00110## S 0 ethyl 91 5-(3-chlorophenyl- amino-carbonyl) ##STR00111## S 0 ethyl 92 5-(3-methoxyphenyl- amino-carbonyl) ##STR00112## S 0 ethyl 93 5-(3-methylphenyl- amino-carbonyl) ##STR00113## S 0 ethyl 94 5-(3,5-dimethoxy- phenyl-amino- carbonyl) ##STR00114## S 0 ethyl 95 5-(2,6-dimethyl- phenyl-amino- carbonyl) ##STR00115## S 0 ethyl 96 5-(3,5-dimethoxy- phenyl) ##STR00116## S 0 ethyl 97 5-(3,4-dimethoxy- phenyl-amino- carbonyl) ##STR00117## S 1 thien-2yl 98 5-(phenyl-oxy) ##STR00118## S 0 ethyl 99 5-(3,4-dimethoxy- phenyl-oxy) ##STR00119## S 0 ethyl 100 5-(phenyl) ##STR00120## S 0 ethyl 101 5-(4-fluorophenyl) ##STR00121## S 0 ethyl 102 5-(4-trifluoromethyl- phenyl) ##STR00122## S 0 ethyl 103 5-(3-(amino- carbonyl)-phenyl) ##STR00123## S 0 ethyl 104 5-(4-methoxy-phenyl) ##STR00124## S 0 ethyl 105 5-(4-trifluoro- methoxy-phenyl) ##STR00125## S 0 ethyl 106 5-(3,4-dimethoxy- phenyl-amino- carbonyl) ##STR00126## S 1 thien-2yl 108 5-(3,4-dimethoxy- phenyl-amino- carbonyl) ##STR00127## S 0 ethyl 109 5-(3,5- di(trifluoromethyl)- phenyl) ##STR00128## S 0 ethyl 110 5-(3,4-dimethoxy- phenyl-amino- carbonyl) ##STR00129## S 0 ethyl 111 5-(4-(amino- carbonyl)-phenyl) ##STR00130## S 0 ethyl 112 5-(benzo[d][1,3] dioxol-5-yl) ##STR00131## S 0 ethyl 113 5-(3-(aminosulfonyl)- phenyl) ##STR00132## S 0 ethyl 114 5-(pyrid-4-yl) ##STR00133## S 0 ethyl 115 5-(3,4-dimethoxy- phenyl-amino- carbonyl) ##STR00134## S 1 amino- carbonyl- 116 5-(2-(amino- carbonyl)-phenyl) ##STR00135## S 0 ethyl 117 5-(3,4-dimethoxy- phenyl-amino- carbonyl) ##STR00136## S 1 thien-2-yl
TABLE-US-00003 TABLE 3 Representative Compounds of Formula (I) ##STR00137## ID No. R.sup.2 ##STR00138## R.sup.A n R.sup.1 107 5-(3,4-dimethoxy- phenyl-amino- carbonyl) ##STR00139## methyl 0 ethyl 118 5-(3,4-dimethoxy- phenyl-amino- carbonyl) ##STR00140## ethyl 1 thien-2-yl
Representative compounds of formula (II) of the present invention are as listed in Table 4, below.
TABLE-US-00004 TABLE 4 Representative Compounds of Formula (II) ##STR00141## ID No. R.sup.2 ##STR00142## * n R.sup.1 43 hydrogen ##STR00143## S 0 ethyl 44 hydrogen ##STR00144## S 0 ethyl
In another embodiment, the present invention is directed to compounds of formula (I) whose IC.sub.50, measured according to the procedure described in Biological Example 1, is less than or equal to about 10 .mu.M, preferably less than or equal to about 5.0 .mu.M, more preferably less than or equal to about 1.0 .mu.M, more preferably less than or equal to about 0.5 .mu.M, more preferably less than or equal to about 0.1 .mu.M.
In another embodiment, the present invention is directed to compounds of formula (II) whose IC.sub.50, measured according to the procedure described in Biological Example 1, is less than or equal to about 10 .mu.M, preferably less than or equal to about 5.0 .mu.M, preferably less than or equal to about 1.0 .mu.M, more preferably less than or equal to about 0.5 .mu.M, more preferably less than or equal to about 0.1 .mu.M.
As used herein, "halogen" shall mean chlorine, bromine, fluorine and iodine.
As used herein, the term "alkyl" whether used alone or as part of a substituent group, shall include straight and branched carbon chain compositions of one to six carbon atoms. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, and the like. The prefix "C.sub.X-Y" wherein X and Y are integers, when used with alkyl shall mean a carbon chain composition of between X and Y carbon atoms. For example, the term "C.sub.1-4alkyl" shall mean a straight or branched carbon chain composition of 1 to 4 carbon atoms.
The description continues in the full USPTO document.
About 4,920 words. The USPTO PDF has it with every drawing.
Fees are due 3.5, 7.5 and 11.5 years after grant. This patent expired on October 8, 2025, so the fee marked "not paid" was the one that went unpaid.
BICYCLIC DERIVATIVES USEFUL AS INHIBITORS OF DPP-1
Filed Dec 2010 · published Jun 2011Bicyclic derivatives useful as inhibitors of DPP-1
Filed Dec 2010 · granted Oct 2013Earlier publications, parents and continuations. None of them can still be enforced, or this patent would not be listed.
Prior art cited by the examiner or applicant. Useful when you check your own idea for novelty.
Everything on this page comes from the documents linked above.
